Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS)

Abstract

Importance: Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition.

Objective: To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women.

Design, setting, and participants: Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017.

Interventions: Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 µg/d transdermal 17β-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month.

Main outcomes and measures: Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated.

Results: The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF.

Conclusions and relevance: Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known.

Trial registration: clinicaltrials.gov Identifier: NCT00154180.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Taylor reports grant support from Pfizer through Yale University and consultation fees from Pfizer. Dr Pal reports personal fees from Merck. Dr Lobo reports consultation fees from Pfizer, Amigen, Teva and grant support from TherapeuticsMD. Dr Black reports grant and personal fees from Novartis, personal fees from Merck, Amgen, and Eli Lilly, outside the present work. Dr Brinton reports personal fees from Alexion, Amarin, Amgen, Aralez, Janssen, Kowa, Merck, Regeneron, Sanofi Aventis, and Takeda. Dr Santoro reports investigator-initiated grant support from Bayer, Inc, and stock options in Menogenix, outside the present work. No other disclosures are reported.

Figures

Figure 1.. CONSORT Flow Diagram of the Ancillary Kronos Early Estrogen Prevention Study (KEEPS)–Sexual Study

Numbers indicate the number of enrolled KEEPS participants completing the Female Sexual Function Inventory questionnaire at that time point.

Figure 2.. Mean Change From Baseline Over Time in the Different Sexual Function Domains, Overall Female Sexual Function Inventory (FSFI) Score, and Sex Hormone–Binding Globulin (SHBG) Levels

P values are presented comparing with placebo. Error bars indicate 95% confidence intervals.

Figure 3.. Treatment Effect Stratified by Baseline Low Sexual Function (LSF) Status

The efficacy of transdermal 17β-estradiol (t-E2) treatment was moderated by baseline LSF. FSFI indicates Female Sexual Function Inventory; o-CEE, oral conjugated equine estrogens. Error bars correspond to standard errors.